Hollow fiber bioreactor cartridges typically include a housing, often cylindrical in shape, that contain a plurality of hollow fibers or filaments. The filaments are formed of a material which allows molecular transport through the filament wall. Such materials typically include polysulfones, cellulose acetates and the like. The cartridges usually define two spaces: an intrafilament space (defined by the lumens of the filaments) and an extrafilament space (defined by exterior of the filaments and the interior of the cartridge housing). The intrafilament space defines a filament flow path which communicates with at least a filament inlet port and a filament outlet port, and the extrafilament space defines an extrafilament flow path which communicates with at least a housing inlet port and a housing outlet port. Communication between the flow paths is limited to molecular transport through the walls of the filaments.
The use of bioreactors containing live cells is known in the art. Typically, the cells are loaded into the extrafilament space and often contained or encapsulated within a supporting matrix. Numerous types of cells have been used, including hepatocytes.
In one mode of use, a biological fluid to be treated, such as blood, is circulated through the filament flow path. If the bioreactor is to act as an artificial liver, the cells are hepatocytes, often harvested from pigs. As the blood flows through the filaments, molecular transport occurs across the filament walls, thereby removing contaminants from the blood. Such systems are often configured with the blood traveling in a fluid circuit from a patient, to the bioreactor and back to the patient. If desired, although not typical, a nutrient solution for the cells can circulated through the extrafilament flow path simultaneously with blood flow through the filaments. The flows may be countercurrent, co-current or crosscurrent flows.
One problem that exists with bioreactors of the type described above is that it is very difficult to construct them with adequate cell uniformity and cell loading density. Thus, bioreactors of the types commonly in use include cells which are seeded into the reactor at low densities and then allowed to grow to confluence. Alternatively, cells are sometimes encapsulated or attached to biocarriers and injected into the bioreactor interior. In each of these embodiments, it has been found to be very difficult to obtain a cell density greater than about 10.sup.5 cells/ml. Since the resulting bioreactors have cell densities several orders of magnitude less than those of normal animal tissue, less than ideal results have been obtained.
As noted above, it has been found to be very difficult to load bioreactors to high cell densities. The basis for this difficulty is as follows. Bioreactor cartridges may include thousands of hollow filaments which are assembled into a cylindrical bundle and then inserted into the cartridge housing. In order to maximize the area of the transport membrane, the filaments are loaded into the housing at very high packing densities. The resulting extrafilament space comprises thousands of very small, narrow passageways between the densely packed filaments. The resulting geometry makes it very difficult to pump viscous fluids through the extrafilament flow path. While lower viscosity fluids can be used, such fluids often do not offer a sufficiently high cell density to produce a device that is viable in clinical settings. However, fluids capable of providing cell densities approaching those of normal animal tissue (i.e., 10.sup.8 cells per milliliter) suffer from an inability to sufficiently infiltrate the extrafilament space. In particular, the use of such high density fluids is often subject to flow shunting in which the fluid will stream directly along the interior wall of the housing, resulting in cell loading of only about 10 to 20% of the available extrafilament space.
Thus, a need exists for a bioreactor that is capable of maintaining living animal cells at a density approaching that of normal animal tissue. A need also exists for a bioreactor that is adapted to be filled with a high cell density in a manner that is simple and results in uniform cell distribution.